Methods for preparing polymers having low residual monomer content

ABSTRACT

Methods are provided for preparing polymer mixtures having low residual monomer content. The methods comprise mixing the at least two polymers in a solvent to form a polymeric mixture, the polymeric mixture comprising at least one residual monomer; and adding an antisolvent to the polymeric mixture so as to separate the at least two polymers from the polymeric mixture, where the residual monomer is soluble in the antisolvent. In some embodiments, methods are provided for preparing at least two polymers having low residual monomer content, the methods comprise adding an antisolvent to a mixture of at least two polymers dissolved in a solvent so as to precipitate the at least two polymers from the solvent and anti-solvent. The methods provided avoid steps in dry blending of polymers and produces polymer blends that have low residual monomer content.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 13/462,395,filed on May 2, 2012, the contents of which is herein incorporated byreference, in its entirety.

FIELD

This application relates to methods for recovering and purifyingpolymers and especially for reducing the monomer content ofbiodegradable polymers.

BACKGROUND

Among various processes of polymerization reactions, solutionpolymerization process is typically applied to synthesize biodegradablepolymers, in which monomers, catalysts, and polymers are all dissolvedin a solvent. The reaction begins with the monomers and the catalystsdissolved in a solvent in a reactor. With the activated catalysts themonomers are continuously added to the growing polymer chain at thecatalyst active site by coordinate covalent bonding. The dissolution ofthe polymer in a solvent is maintained to perform the reaction in asingle homogeneous liquid phase.

When the reaction is finished, the solution in a reactor becomes amixture containing the polymer obtained by the synthesis, unreactedmonomers, the solvent, and a small amount of catalyst. Accordingly,after the reaction, a process for selectively recovering the polymerfrom the solution is required.

The presence of monomers in the synthesis of polymers is frequentlyproblematic. For example, in the synthesis of biodegradable polymerssuch as homopolymers or copolymers based on lactide (L-lactide,D-lactide, DL-lactide, meso-lactide), glycolide, epsilon-caprolactone,dioxanone, trimethylene carbonate, delta-valerolactone,gamma-butyrolactone the presence of monomers is undesirable for variousreasons. In many instances monomers decompose more rapidly thanbiodegradable polymers on exposure to moisture. Consequently, theimplantation of monomer-containing biodegradable polymers wouldtherefore lead to a greatly accelerated breakdown of the material in thebody. For the same reason, the stability in storage ofmonomer-containing polymers and implants or pharmaceutical formulationsproduced therefrom is markedly impaired.

It is well known that drug depots are prepared by well knownthermoplastic processes such as melt extrusion or injection molding. Thestability of biodegradable polymers is also impaired duringthermoplastic processing if residual contents of monomers are present.

In other instances, the encapsulation behavior of non-purifiedbiodegradable polymers is different from that of purified polymers, asare the release behavior and the breakdown behavior. Encapsulated activeingredients, such as peptides, can become damaged or destroyed as aresult of the greater amount of free acid present in monomercontaminated polymers compared to purified polymers.

During the synthesis reactions, the residual monomer content of thecrude polymer is often difficult to control. Variability in the residualmonomer content then automatically also leads to intolerablebatch-to-batch variations in the breakdown rate, the stability instorage and the processing stability, so materials of reproduciblequality cannot be obtained without a subsequent purification step toreduce the amount of residual monomers.

It would therefore be desirable to develop improved polymer recovery andpurification methods that minimize the presence of monomers in meltextrudable polymers and at the same time reduce the number of unitoperations required to produce the same thereby reducing both the timeand cost of manufacturing.

SUMMARY

Methods are provided for recovering at least two polymers includingdissolving the at least two polymers in a solvent to form a polymericmixture which also includes at least a monomer. An antisolvent, which isa solvent for the monomer but not a solvent for the at least twopolymers, is then added to the polymeric mixture and the at least twopolymers precipitate out of the polymeric solution. In this way, theprecipitated product has low residual monomer content.

The at least two polymers present in the precipitate are then separatedfrom the remaining monomeric solution by decanting, centrifugation,microfiltration, ultrafiltration, sieving or a combination thereof. Onceformed the precipitate including the at least two polymers can be driedby evaporation with air or nitrogen or freeze-drying.

The polymeric mixture containing the at least two polymers can behomogenous and form a polymeric solution in which the at least twopolymers have similar solubilities in the solvent.

In some embodiments the at least two polymers recovered according tomethods of the present disclosure comprise, consist essentially of, orconsist of biodegradable polymers selected from polylactide (PLA) or oneor more of poly(lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,L-lactide-co-ε-caprolactone, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, poly(D,L-lactide-co-caprolactone), poly (L-lactide-co-caprolactone), or acombination thereof. In other embodiments, the at least two polymerscomprise, consist essentially of, or consist ofpoly(lactic-co-glycolide) and said poly(lactic-co-glycolide) comprises amixture of polyglycolide and polylactide. In yet other embodiments, theat least two polymers present in the polymeric mixture comprise, consistessentially of, or consist of more polylactide than polyglycolide.

In some embodiments, the at least two polymers are derived from one ormore monomers selected from lactide (L-lactide, D-lactide, DL-lactide,meso-lactide), glycolide, trimethylene carbonate, epsilon-caprolactone,gamma-butyrolactone, dioxanone, delta-valerolactone, polymerisableheterocycles or polyethylene glycols.

Solvents capable of dissolving the at least two polymers include withoutlimitation n-hexane, cyclohexane, heptanes, methylene chloride, ethylacetate, acetone, polyethylene glycols as esters or ethers,polyethoxylated fatty acids, hydroxylated fatty acids, fatty alcohols,polyethoxylated castor oil, polyethoxylated hydrogenated castor oil,polyethoxylated fatty acid from castor oil, polyethoxylated fatty acidfrom hydrogenated castor oil, Cremophor, Myrj, Polyoxyl 40 stearate,Emerest 2675, Lipal 395, Tween, Span and HCO 50, glycerin,N,N-dimethylacetamide, ethyl alcohol, denatured alcohol, ester, acetone,transcutol or a combination thereof. Useful antisolvents serve assolvents for the monomer but are non-solvents for the at least twopolymers and include without limitation water, ethanol, methanol,supercritical carbon dioxide, supercritical nitrogen, supercriticalwater or mixtures thereof.

In some embodiments, it is contemplated that the polymeric mixtureincludes more than two polymers, for example, a first polymer in anamount of about 10%, a second polymer in an amount of about 20%, a thirdpolymer in an amount of about 50% and a fourth polymer of about 20%.

In some embodiments, the methods provided avoid or limit the dryblending steps when blending polymers and/or co-polymers.

In another embodiment, methods are provided for recovering at least twopolymers comprising, consisting essentially of, or consisting ofdissolving the at least two polymers in a solvent to form a polymericmixture, adding an antisolvent to the polymeric mixture to form aprecipitate of the at least two recovered polymers and separating the atleast two recovered polymers from the remaining monomeric solution. Thepolymeric mixture includes a monomer and the antisolvent is a solventfor the monomer and a non-solvent for the at least two polymers.

In other embodiments, the at least two biodegradable polymers recoveredaccording to methods described in this disclosure are useful in themanufacture of drug depots especially by hot melt extrusion. Drug depotsmanufactured from the at least two polymers recovered and/or purifiedaccording to methods described in this disclosure: (i) consist of onlythe active pharmaceutical ingredient (or one or more of itspharmaceutically acceptable salts) and the biodegradable polymer(s); or(ii) consist essentially of the active pharmaceutical ingredient (and/orone or more of its pharmaceutically acceptable salts) and thebiodegradable polymer(s); or (iii) comprise the active pharmaceuticalingredient (and/or one or more of its pharmaceutically acceptablesalts), and the biodegradable polymer(s) and one or more other activeingredients, surfactants, excipients or other ingredients orcombinations thereof. When there are other active ingredients,surfactants, excipients or other ingredients or combinations thereof inthe formulation, in some embodiments these other compounds orcombinations thereof comprise less than 50 wt. %. less than 40 wt. %,less than 30 wt. %, less than 20 wt. %, less than 19 wt. %, less than 18wt. %, less than 17 wt. %, less than 16 wt. %, less than 15 wt. %, lessthan 14 wt. %, less than 13 wt. %, less than 12 wt. %, less than 11 wt.%, less than 10 wt. %, less than 9 wt. %, less than 8 wt. %, less than 7wt. %, less than 6 wt. %, less than 5 wt. %, less than 4 wt. %, lessthan 3 wt. %, less than 2 wt. %, less than 1 wt. % or less than 0.5 wt.%.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

Reference will now be made in detail to certain embodiments of theinvention. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

BRIEF DESCRIPTION OF THE DRAWING

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawing where:

FIG. 1 is a schematic of the process in accordance with the principlesof the present disclosure.

It is to be understood that the FIGURE are not drawn to scale. Further,the relation between objects in a FIGURE may not be to scale, and may infact have a reverse relationship as to size. The FIGURE is intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

DEFINITIONS

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

Generally, the term “biodegradable polymer” means a synthetic or anaturally derived biodegradable, biocompatible polymer that may beabsorbed (resorbed) once implanted in a living mammalian body. In thepresent application biodegradable polymer refers to syntheticallyderived polymers. Synthetic biodegradable polymers include, but are notlimited to, polyethylene glycol (PEG), polyvinyl alcohol (PVA),polyorthoester (POE), polylactic acid (PLA), polyglycolic acid (PGA),polyactic-glycolic acid (PLGA) and combinations thereof.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof. In some embodiments, thedrug depot has a modulus of elasticity in the range of about 1×10² toabout 6×10⁵ dyn/cm², or 2×10⁴ to about 5×10⁵ dyn/cm², or 5×10⁴ to about5×10⁵ dyn/cm². In some embodiments, the drug depot is in solid form andcomprises the mixed monoamine reuptake inhibitor.

A “drug depot” is the composition in which a drug or activepharmaceutical ingredient is administered to the body. Thus, a drugdepot may comprise a physical structure to facilitate implantation andretention in a desired site (e.g., a disc space, a spinal canal, atissue of the patient, particularly at or near a site of chronic pain,etc.). The drug depot may also comprise the drug itself. The term “drug”as used herein is generally meant to refer to any substance that altersthe physiology of a patient. The term “drug” may be used interchangeablyherein with the terms “therapeutic agent,” “therapeutically effectiveamount,” and “active pharmaceutical ingredient” or “API.” It will beunderstood that unless otherwise specified a “drug” formulation mayinclude more than one therapeutic agent, wherein exemplary combinationsof therapeutic agents include a combination of two or more drugs. Thedrug provides a concentration gradient of the therapeutic agent fordelivery to the site. In various embodiments, the drug depot provides anoptimal drug concentration gradient of the therapeutic agent at adistance of up to about 0.01 cm to about 20 cm from the administrationsite and comprises the active pharmaceutical ingredient. A drug depotmay also include a pump or pellet.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain or spasticity, improvement in the condition throughmuscle relaxation, etc. The dosage administered to a patient can be assingle or multiple doses depending upon a variety of factors, includingthe drug's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), and extent of symptoms, concurrenttreatments, frequency of treatment and the effect desired. In someembodiments the formulation is designed for immediate release. In otherembodiments the formulation is designed for sustained release. In otherembodiments, the formulation comprises one or more immediate releasesurfaces and one or more sustained release surfaces.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, etc.) can break down or degrade within thebody to non-toxic components after or while a therapeutic agent has beenor is being released. By “bioerodible” it is meant that the depot willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The phrases “sustained release” and “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in vivo of the drug depot,or a matrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s).

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in one or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example a bolus or immediate release formulation of an activepharmaceutical ingredient may be placed at or near the target site and asustain release formulation may also be placed at or near the same site.Thus, even after the bolus becomes completely accessible, the sustainrelease formulation would continue to provide the active ingredient forthe intended tissue.

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first twenty-four toseventy-two hours after implantation. “Initial burst” or “burst effect”or “bolus dose” refers to the release of therapeutic agent from thedepot during the first twenty-four hours to seventy-two hours after thedepot comes in contact with an aqueous fluid (e.g., synovial fluid,cerebral spinal fluid, etc.). In some embodiments, the steroid can alsobe administered in a bolus dose. The “burst effect” is believed to bedue to the increased release of therapeutic agent from the depot. Inalternative embodiments, the depot (e.g., gel) is designed to avoid orreduce this initial burst effect (e.g., by applying an outer polymercoating to the depot).

The term “implantable” as utilized herein refers to a biocompatibledevice (e.g., drug depot) retaining potential for successful placementwithin a mammal. The expression “implantable device” and expressions ofthe like import as utilized herein refers to an object implantablethrough surgery, injection, or other suitable means whose primaryfunction is achieved either through its physical presence or mechanicalproperties.

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 0.1cm, or preferably within about 10 cm, for example) thereto. For example,the drug dose delivered locally from the drug depot may be, for example,10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9% or 99.999%less than the oral dosage or injectable dose. In turn, systemic sideeffects, such as for example, liver transaminase elevations, hepatitis,liver failure, myopathy, constipation, etc. may be reduced oreliminated. In some embodiments, the depot is not to be administered ator near the eye.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

“Targeted delivery system” provides delivery of one or more drugsdepots, gels or depots dispersed in the gel having a quantity oftherapeutic agent that can be deposited at or near the target site asneeded for treatment of pain, inflammation or other disease orcondition.

The abbreviation “DLG” refers to poly(DL-lactide-co-glycolide).

The abbreviation “DL” refers to poly(DL-lactide).

The abbreviation “LG” refers to poly(L-lactide-co-glycolide).

The abbreviation “CL” refers to polycaprolactone.

The abbreviation “DLCL” refers to poly(DL-lactide-co-caprolactone).

The abbreviation “LCL” refers to poly(L-lactide-co-caprolactone).

The abbreviation “G” refers to polyglycolide.

The abbreviation “PEG” refers to poly(ethylene glycol).

The abbreviation “PGA” refers to polyglycolic acid.

The abbreviation “PLGA” refers to poly(lactide-co-glycolide) also knownas poly(lactic-co-glycolic acid), which are used interchangeably.

The abbreviation “PLA” refers to polylactide.

The abbreviation “POE” refers to poly(orthoester).

The abbreviation “PVA refers to polyvinyl alcohol.

Biodegradable polymers useful in the preparation of drug depots can beeasily hot melt extrudable. In order to produce hot melt extrudablepolymers many processes include three unit operations, (i) milling orgrinding to reduce polymer particle size; (ii) homogenous blending whenmore than one polymer is used; and (iii) reduction of the residualmonomer. The presence of monomers in biodegradable polymers interfereswith the melt extrusion process and results in the production ofunstable drug depots. It has now been surprisingly found that accordingto the recovery and purification methods provided in this application,biodegradable polymers having an insignificant amount of monomers can beprovided. The purification methods of this application provide a uniqueway of homogeneously mixing at least two or more polymers with similarsolubilities while also combining three unit operations into a singleprocessing step to reduce both time and cost of manufacturing.

In some embodiments a method for recovering at least two polymers havingsimilar solubilities is provided, the method including dissolving the atleast two or more polymers in a solvent to form a polymeric mixture,which mixture contains at least a monomer; adding an antisolvent inwhich the monomer is solvent but which is a non-solvent or ant-solventfor the at least two polymers to the polymeric mixture so as to form aprecipitate of the at least two polymers and a monomeric solutioncontaining at least one monomer. The precipitate of the at least twopolymers is subsequently recovered from the monomeric solution toprovide polymers of high purity. The process described in thisdisclosure is particularly useful to produce biodegradable polymers ofhigh purity useful in the manufacture of drug depots by hot meltextrusion.

It will be understood by those of ordinary skill in the art that thesolvent is the substance that the polymer is able to dissolve in. Thepolymer is soluble in the solvent. However, when an anti-solvent isintroduced for the polymer, the monomer is soluble in the anti-solventfor the polymer. Because the polymer is not soluble or insoluble in theanti-solvent, the polymer will precipitate out of the liquid and therecan be highly pure polymer or blends of polymer recovered in a product.This product can be used to make the medical device (e.g., drug depot).

In some embodiments, the solubility range of the polymer in the solventis greater than from about 0.5 mg/ml to greater than about 2 mg/ml orgreater than 1 mg/ml. In some embodiments, the polymer is insoluble inthe solvent when it is less than 0.1 mg/ml, for example from about 0.05mg/ml to about 0.01 mg/ml.

In various embodiments, the polymer particle size used is from about 5to 500 micrometers, however, in various embodiments ranges from about 10micron to 350 microns may be used. In some embodiments, the polymerparticle size range comprises from about 25 micrometer to about 300micrometers. In some embodiments, the polymer particle size rangecomprises from about 50 micrometer to about 200 micrometers.

An example of an embodiment of the method described in this disclosureis set forth in FIG. 1, wherein 1 represents the inflow of at least twopolymers into the reaction vessel 3, while 2 is the inflow of theantisolvent to the reaction vessel 3 and 4 represents the outflow of aprecipitate of the at least two polymers after separation from thereaction vessel 3. FIG. 1 shows a unique way of homogeneously mixing atleast two or more polymers with similar solubilities which processefficiently and economically combines the unit operations of particlesize reduction and residual monomer removal into a single step.

In some embodiments, the moist precipitate of at least two polymers isseparated effectively by means of gravity and subsequently theprecipitate can be dried by evaporation with air, nitrogen orfreeze-drying. Other means of separation of the precipitate containingthe at least two polymers and the monomeric solution include decanting,centrifugation, microfiltration, ultrafiltration, sonication, sieving ora combination thereof. After the drying, the solvent and/or moisturecontent of the at least two biodegradable polymers is less than 2%,values of below 1%, in particular values of below 0.5% and less than0.1% being achieved under beneficial settings.

The at least two polymers that can be purified according to the methodsprovided herein include without limitations (i) polylactide (PLA) or(ii) one or more of poly(lactide-co-glycolide) (PLGA), polylactide(PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,L-lactide-co-ε-caprolactone, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, poly(D,L-lactide),poly(L-lactide), poly (D-L-lactide-co-caprolactone), poly(L-lactide-co-caprolactone) or a combination thereof.

In other aspects, the at least two polymers contain one or more unitsderived from lactide (L-lactide, D-lactide, D,L-lactide, meso-lactide),glycolide, trimethylene carbonate, epsilon-caprolactone,gamma-butyrolactone, dioxanone, delta-valerolactone and/or similarpolymerisable heterocycles and/or polyethylene glycols. Particularlypreferred are polymers composed of D,L-lactide or copolymers ofD,L-lactide and glycolide having any desired composition or a blockcopolymer of D,L-lactide, or D,L-lactide-co-glycolide having any desiredcomposition and polyethylene glycol.

In yet other embodiments, the at least two biodegradable polymersinclude a mixture of polyglycolide and polylactide. In other embodimentsthe polymeric mixture resulting from dissolving the at least twopolymers includes more polylactide than polyglycolide.

In various embodiments, the at least two polymers are polymer gelsprepared by copolymerizing monomers including (meth)acrylic acid,(meth)acrylamide, N-substituted (meth)acrylamides and unsaturatedcarboxylic acid.

In other embodiments, the method described in this application can beutilized to purify cyclic olefin polymers whose monomers typically showvery high boiling point temperature (150° C. or more) and polymers nothaving a specific melting point temperature. Cyclic olefin copolymersare produced by chain copolymerization of cyclic monomers such as8,9,10-trinorborn-2-ene (norbornene) or1,2,3,4,4a,5,8,8a-octahydro-1,4:5,8-dimethanonaphthalene(tetracyclododecene) with ethene.

While the purifying method requires the homogeneous mixing of at leasttwo polymers, other polymeric combinations are also contemplated. Forexample, a blend of biodegradable polymers includes a first polymer inan amount of about 10%, a second polymer in an amount of about 20%, athird polymer in an amount of about 50% and a fourth polymer of about20%.

The at least two polymers are homogeneously mixed by dissolving theminto a solvent in which the at least two polymers are soluble andpreferably have similar solubilities, thereby forming a polymericmixture, which in some embodiments can be a polymeric solution. In thepolymeric mixture the at least two polymers mix at molecular level.

Useful solvents for dissolving the at least two polymers include withoutlimitations n-hexane, cyclohexane, heptanes, methylene chloride, ethylacetate, acetone or combinations thereof. For effective recovery orpurification of the at least two polymers, it is preferable that themonomers still present in the polymeric mixture are insoluble in thesolvents utilized to dissolve the at least two polymers. However, inorder to purify effectively the at least two polymers, the monomersstill present in the polymeric mixture must be soluble in anantisolvent, which when added to the polymeric solution causes theprecipitation of the at least two polymers.

Suitable antisolvents include without limitation water, ethanol,methanol or combinations thereof. Water as the antisolvent isparticularly effective since it is non-toxic, non-explosive,cost-effective and environmentally acceptable. In some embodiments, thesolvent comprises supercritical water, supercritical carbon dioxide,super critical nitrogen or a combination thereof.

The at least two polymers are recovered from the polymeric mixtureobtained after polymerization by using a precipitation phenomenon that apolymer dissolved in a solvent precipitates out in a solid form when theantisolvent having a very low solubility of polymer is added to thepolymeric mixture. The precipitation phenomenon means that when anantisolvent is added to a polymer material dissolved in a liquid by asolvent, when the anti-solvent is added which cannot dissolve thepolymer material, but can dissolve the monomer, the polymer material isprecipitated out in a solid form. The antisolvent is a material, whichcan be mixed with the solvent of the polymer mixture but is anon-solvent with respect to the polymer material to be separated. Themonomer that is contained in the polymer is, however, soluble in theantisolvent. If the antisolvent is used in a sufficiently large amount,the polymer material is precipitated while coming into contact with theantisolvent. Accordingly, the precipitation phenomenon relates to aphase-conversion reaction where the liquid polymer phase is rapidlyconverted into solid phase. However, the monomer will remain in themixture.

With respect to the at least two polymers present in the polymericmixture, the precipitation phenomenon is used in order to recover the atleast two polymers in the polymer mixture synthesized after thepolymerization reaction. A batch type dropping method can be used tofacilitate the precipitation phenomenon. Examples of the dropping methodmay include a forward dropping method where a polymerization mixture isadded to an antisolvent as a liquid droplet, and a backward droppingmethod where an antisolvent is added to a polymerization solution as aliquid droplet. In a polymerization process of biodegradable polymers,the above-mentioned dropping precipitation method is used and a singlekind of antisolvent for complete precipitation or two kinds ofantisolvents for partial precipitation followed by completeprecipitation are used to perform the process. The reason why two ormore kinds of antisolvents are used during the dropping method is thatit is easy to obtain the polymer in a particle form as compared to thecase of a single kind of antisolvent. First, the antisolvent for partialprecipitation is added to the polymerization mixture to partiallyprecipitate the polymer. At this time, the polymerization mixture ischanged from a clear and transparent liquid state to a semi-transparentand frosty state. Next, a large amount of antisolvent for completeprecipitation is added to completely precipitate the polymer particles.The at least two polymers which are dissolved in the polymerizationmixture are precipitated out in a solid form if the antisolvent is addedthereto. In respect to the dropping method, very small solid particlesare first formed during the partial precipitation, and the formed solidparticles coagulate to each other to form larger size particles when theantisolvent for complete precipitation is further added. In this case,it is presumed that the particle size is determined depending on thesupply rate of the antisolvent and the rpm of an impeller in aprecipitation reactor or the tip speed of the impeller. A repulsiveforce against a cohesive force between particles is generated due to ashearing force from the impeller. Accordingly, if the cohesive forcebetween particles is larger than the repulsive force generated due tothe shearing force of the impeller, the particle size will becontinuously increased. Meanwhile, as the precipitation of particlesreaches the complete precipitation, the cohesive force between particlesis decreased. When particles have been completely precipitated, thecohesive force is hardly generated between particles since salvationeffect by solvent is blocked by antisolvent.

In a dropping method, however, an antisolvent is gradually supplied ontothe surface of a polymer solution, while high shearing force isgenerated near the impeller and a relatively low shearing force isgenerated on the surface of the solution. Therefore, if particles arestrongly cohered on the surface of the solution, there is a possibilitythat the polymer is obtained in the form of not particles but a cake.

In some embodiments, the temperature, pH, and other characteristics ofthe solvent and antisolvent can be used to optimize the purificationprocess described herein. For example, maintaining the polymeric mixtureat a temperature from about 15° C. to about 100° C. increases the rateof dissolution. Similarly, adding the antisolvent at a temperature fromabout 15° C. to about 100° C. accelerates the formation of a precipitatecontaining the at least two polymers or polymer blends with copolymers.The process of this application also contemplates adjusting the pH ofthe polymeric mixture and/or the monomeric solution to optimize theconditions under which the at least two polymers are recovered. Forexample, maintaining the polymeric mixture at a pH of 4-6 enhances thedissolution of the at least two polymers. Similarly, maintaining the pHof the antisolvent at a pH of about 7 enhances the solubility of themonomers and accelerates the precipitation process.

In some embodiments, in order to increase the molecular dispersion ofthe raw biodegradable polymers, other ingredients can be added to thepolymeric solution, such as for example, other co-solvents, wettingagents and dispersants. In various embodiments, dispersants can includegas such as carbon dioxide or surfactants.

Useful surfactants include anionic, cationic, amphoteric, non-ionicsurfactants or combinations thereof. A non-limiting list of surfactantswhich may be used in accordance with the methods described hereininclude long-alkyl-chain sulfonates, alkyl aryl sulfonates, dialkylsodium sulfosuccinates, alkyl sulfates, quaternary ammonium salts, fattyalcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esterssuch as mono-, di- and triglycerides; and fatty acid esters of fattyalcohols and other alcohols such as propylene glycol, polyethyleneglycol, sorbitan, sucrose and cholesterol; polyoxyethylene glyceryl,steroidal esters, polyoxypropylene esters, and combinations thereof.

After the at least two polymers are recovered and purification has beencarried out using the methods according this application, a residualmonomer content of less than 1%, preferably less than 0.5%, mostpreferably less than 0.1% can be achieved.

The polymers, before the method is performed, comprise one or moremonomeric units (e.g., monomers, dimmers, trimers, tetramers, pentamers,hexamers, or other small oligomers) that are not part of the polymerchain, however, the monomer interacts with the polymer chain andrepresents monomeric impurities. An impurity in the polymer, includes,but is not limited to an unintended constituent present in themanufactured polymer substance. It may, in some embodiments, originatefrom the starting materials, such as the monomers, or other reactants,or be the result of secondary or incomplete reactions during theproduction process such as oligomers. While it is present in the polymerit was not intentionally added. Examples of such impurities in a polymerinclude unreacted monomers, monomer intermediates, other reactants,oligomers, residual polymerization catalysts, or other contaminants fromthe manufacturing process. These unreacted or residual monomers can beassociated with the polymer.

The recovered polymer, or polymer blend after it is recovered issubstantially pure, which means that the polymer is substantially freefrom residual monomer content. In various embodiments, the polymer is atleast 95% free, at least 99% free, at least 99.5% free or at least 99.9%free of residual monomer materials. Polymer is considered to besubstantially pure if it is at least 95%, at least 99%, at least 99.5%,at least 99.9% free from residual monomer material. Therefore, there isa low residual levels of monomer content of less than 5%, less than2.5%, less than 1%, less than 0.5%, or less than 0.1% w/w, w/v, or v/vin the polymer.

As a result of the methods described herein, the recovered at least twopolymers have smaller polymer domain. For example, while thenon-purified polymers contain polymer domains of more than 1 cm, therecovered, purified polymers have polymer domains of less than 0.1 mm,preferably less than 0.05 mm, most preferably less than 0.025 mm. Insome embodiments, if you mix the at least two polymers using a dryblending technique, the domain size would be similar to the startingparticle size. In this case, you can have domain sizes that are on theorder of a molecular dispersion of the polymers

In some embodiments, the polymers recovered utilizing the methods of thepresent application are a free flowing powder having a smaller particlesize than the non-purified polymers. For example, the raw, at least twopolymer mixture can have a particle size from about 400 μm to about 1000μm, from about 500 μm to about 2000 or from about 1000-4000 μm while therecovered polymers have a particle size from about 25 μm to about 300μm. In various embodiments, the recovered biodegradable polymer particlesize, which may be in powdered form is from about 5 to 30 micrometers.In some embodiments, the polymer can be obtained a pellet with dimensionof from about 0.5-2.0 mm diameter to and about 1-6 mm length.

In some embodiments, at least 75% of the particles of the polymer have asize from about 10 micrometer to about 300 micrometers. In someembodiments, at least 85% of the particles have a size from about 10micrometer to about 300 micrometers. In some embodiments, at least 95%of the particles have a size from about 10 micrometer to about 300micrometers. In some embodiments, all of the particles have a size fromabout 10 micrometer to about 300 micrometers.

In some embodiments, at least 75% of the particles of the recoveredbiodegradable polymers have a size from about 20 micrometer to about 180micrometers. In some embodiments, at least 85% of the particles have asize from about 20 micrometers to about 180 micrometers. In someembodiments, at least 95% of the particles have a size from about 20micrometer to about 180 micrometers. In some embodiments, all of theparticles of the recovered biodegradable polymers have a size from about20 micrometer to about 180 micrometers. In some embodiments, at least80% of the particles have a size from 5 microns to about 100 microns ona volume basis.

The biodegradable polymers recovered according to the methods describedherein can be subjected to hot-melt extrusion, spray drying, injectionmolding to be shaped into a variety of shapes such as microparticles,nanoparticles and the like. A particularly preferred use of therecovered biodegradable polymers provides for the production ofpharmaceutical formulations or resorbable implants, such as, forexample, drug depots.

In various embodiments, a drug depot manufactured from biodegradablepolymers selected from the at least two polymers recovered and purifiedaccording to methods described in this disclosure include, for example,poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or copolymers thereof or acombination thereof.

In some embodiments, the drug depot comprises one or more polymers(e.g., PLA, PLGA, etc.) having a MW of from about 15,000 to about150,000 Da or from about 25,000 to about 100,000 Da. In someembodiments, the drug depot comprises one or more polymers (poly(D-lactide) caprolactone, etc.) having an inherent viscosity of 0.6 toabout 1.0 dL/gm and a MW of 50,000 to about 125,000 Da, or from 50,000to about 70,000 Da.

As persons of ordinary skill in the art are aware, an implantable depotcompositions having a blend of polymers with different end groups areused the resulting formulation will have a lower burst index and aregulated duration of delivery. For example, one may use polymers withacid (e.g., carboxylic acid) and ester end groups (e.g., methyl or ethylester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL(glycolic acid/polycaprolactone) ratio for a given polymer) there willbe a resulting depot composition having a regulated burst index andduration of delivery. For example, a depot composition having a polymerwith a L/G ratio of 50:50 may have a short duration of delivery rangingfrom about two days to about one month; a depot composition having apolymer with a L/G ratio of 65:35 may have a duration of delivery ofabout two months; a depot composition having a polymer with a L/G ratioof 75:25 or L/CL ratio of 75:25 may have a duration of delivery of aboutthree months to about four months; a depot composition having a polymerratio with a L/G ratio of 85:15 may have a duration of delivery of aboutfive months; a depot composition having a polymer with a L/CL ratio of25:75 or PLA may have a duration of delivery greater than or equal tosix months; a depot composition having a terpolymer of CL/G/L with Ggreater than 50% and L greater than 10% may have a duration of deliveryof about one month and a depot composition having a terpolymer of CL/G/Lwith G less than 50% and L less than 10% may have a duration months upto six months. In general, increasing the G content relative to the CLcontent shortens the duration of delivery whereas increasing the CLcontent relative to the G content lengthens the duration of delivery.Thus, among other things, depot compositions having a blend of polymershaving different molecular weights, end groups and comonomer ratios canbe used to create a depot formulation having a lower initial burst and aregulated duration of delivery.

In various embodiments, the polymer may have a pre-dosed viscosity inthe range of about 1 to about 2000 centipoise (cps), 1 to about 200 cps,or 1 to about 100 cps. The depot may have a modulus of elasticity in therange of about 1×−10 ² to about 6×10⁵ dynes/cm², or 2×10⁴ to about 5×10⁵dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In various embodiments, the polymer used in the depot has a molecularweight, as shown by the inherent viscosity, from about 0.10 dL/g toabout 1.2 dL/g or from about 0.10 dL/g to about 0.40 dL/g. Other IVranges of the polymers in the depot include but are not limited to about0.05 to about 0.15 dL/g, about 0.10 to about 0.20 dL/g, about 0.15 toabout 0.25 dL/g, about 0.20 to about 0.30 dL/g, about 0.25 to about 0.35dL/g, about 0.30 to about 0.35 dL/g, about 0.35 to about 0.45 dL/g,about 0.40 to about 0.45 dL/g, about 0.45 to about 0.50 dL/g, about 0.50to about 0.70 dL/g, about 0.60 to about 0.80 dL/g, about 0.70 to about0.90 dL/g, about 0.80 to about 1.00 dL/g, about 0.90 to about 1.10 dL/g,about 1.0 to about 1.2 dL/g, about 1.1 to about 1.3 dL/g, about 1.2 toabout 1.4 dL/g, about 1.3 to about 1.5 dL/g, about 1.4 to about 1.6dL/g, about 1.5 to about 1.7 dL/g, about 1.6 to about 1.8 dL/g, about1.7 to about 1.9 dL/g, and about 1.8 to about 2.1 dL/g.

In some embodiments, the drug depot is solid and has a modulus ofelasticity in the range of about 1×−10² to about 6×10⁵ dynes/cm², or2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfate,sodium bisulfite, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

In a depot the active drug may also be administered with non-activeingredients. These non-active ingredients may have multi-functionalpurposes including the carrying, stabilizing and controlling the releaseof the therapeutic agent(s). The sustained release process, for example,may be by a solution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable.

Exemplary excipients that may be formulated with an activepharmaceutical ingredient in addition to the biodegradable polymerinclude but are not limited to MgO (e.g., 1 wt. %), mPEG, TBO-Ac, PEG,Span-65, Span-85, pluronic F127, sorbitol, cyclodextrin, maltodextrin,pluronic F68, CaCl₂, trehalose, mannitol, dextran, and combinationsthereof. In some embodiments, the excipients comprise from about 0.001wt. % to about 50 wt. % of the formulation. In some embodiments, theexcipients comprise from about 0.001 wt. % to about 40 wt. % of theformulation. In some embodiments, the excipients comprise from about0.001 wt. % to about 30 wt. % of the formulation. In some embodiments,the excipients comprise from about 0.001 wt. % to about 20 wt. % of theformulation. In some embodiments, the excipients comprise from about0.001 wt. % to about 10 wt. % of the formulation. In some embodiments,the excipients comprise from about 0.001 wt. % to about 5 wt. % of theformulation. In some embodiments, the excipients comprise from about0.001 wt. % to about 2 wt. % of the formulation.

In various embodiments, the non-active ingredients will be durablewithin the tissue site for a period of time equal to or greater than(for biodegradable components) or greater than (for non-biodegradablecomponents) the planned period of drug delivery.

In some embodiments, the depot material may have a melting point orglass transition temperature close to or higher than body temperature,but lower than the decomposition or degradation temperature of thetherapeutic agent. In some embodiments, a plasticizer is used to lowerthe glass translation temperature in order to affect the stability ofthe drug depot. However, the pre-determined erosion of the depotmaterial can also be used to provide for slow release of the loadedtherapeutic agent(s). Non-biodegradable polymers include but are notlimited to PVC and polyurethane.

In some embodiments, the drug depot may not be fully biodegradable. Forexample, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics, methacrylates, poly (N-isopropylacrylamide), PEO-PPO-PEO(pluronics) or combinations thereof. Typically, these types of drugdepots may need to be removed after a certain amount of time.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial, the mechanism of the degradation process can be hydrolyticalor enzymatical in nature, or both. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion).

In various embodiments, the depot may comprise a bioerodible, abioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release, or sustained release of the drug. Examples ofsuitable sustained release biopolymers include but are not limited topolymers recovered and purified according to methods described in thisapplication such as poly (alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG),polyethylene glycol (PEG) conjugates of poly (alpha-hydroxy acids),poly(orthoester)s (POE), polyaspirins, polyphosphagenes, collagen,starch, pre-gelatinized starch, hyaluronic acid, chitosans, gelatin,alginates, albumin, fibrin, vitamin E analogs, such as alpha tocopherylacetate, d-alpha tocopheryl succinate, D,L-lactide, or L-lactide,ε-caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA),PVA-g-PLGA, PEGT-PBT copolymer (polyactive), PEO-PPO-PAA copolymers,PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblockcopolymers, SAIB (sucrose acetate isobutyrate) or combinations thereof.As persons of ordinary skill are aware, mPEG may be used as aplasticizer for PLGA, but other polymers/excipients may be used toachieve the same effect. mPEG imparts malleability to the resultingformulations. In some embodiments, these biopolymers may also be coatedon the drug depot to provide the desired release profile. In someembodiments, the coating thickness may be thin, for example, from about5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 microns to thicker coatings 60,65, 70, 75, 80, 85, 90, 95, 100 microns to delay release of the drugfrom the depot. In some embodiments, the range of the coating on thedrug depot ranges from about 5 microns to about 250 microns or 5 micronsto about 200 microns to delay release from the drug depot.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a flat surfacesuch as a disc, film or sheet (e.g., ribbon-like) or the like.Flexibility may be a consideration so as to facilitate placement of thedrug depot. In various embodiments, the drug depot can be differentsizes, for example, the drug depot may be a length of from about 0.5 mmto 5 mm and have a diameter of from about 0.01 to about 4 mm. In variousembodiments, as the diameter decreases, the surface area that comes incontact with the bodily fluid of the depot increases and thereforerelease of the drug from the depot increases. In various embodiments,the drug depot may have a layer thickness of from about 0.005 to 1.0 mm,such as, for example, from 0.05 to 0.75 mm.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium phosphate, bismuth, iodine, tantalum, tungsten, and/ormetal beads or particles. In various embodiments, the radiographicmarker could be a spherical shape or a ring around the depot.

Gel

The at least two polymers recovered and/or purified according to methodsdescribed herein are also useful to form drug delivery systemscomprising or comprised into a drug depot.

In one embodiment, a depot comprises an adherent gel comprising anactive pharmaceutical ingredient that is evenly distributed throughout agel. The gel may be of any suitable type, as previously indicated, andshould be sufficiently viscous so as to prevent the gel from migratingfrom the targeted delivery site once deployed; the gel should, ineffect, “stick” or adhere to the targeted tissue site. The gel may, forexample, solidify upon contact with the targeted tissue or afterdeployment from a targeted delivery system. The targeted delivery systemmay be, for example, a syringe, a catheter, needle or cannula or anyother suitable device. The targeted delivery system may inject the gelinto or on the targeted tissue site. The therapeutic agent may be mixedinto the gel prior to the gel being deployed at the targeted tissuesite. In various embodiments, the gel may be part of a two-componentdelivery system and when the two components are mixed, a chemicalprocess is activated to form the gel and cause it to stick or to adhereto the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×−10² to about 3×10⁵dynes/cm², or 2×10⁴ to about 2×10⁵ dynes/cm², or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×−10² to about 2×10⁶ dynes/cm², or 1×10⁵ to about 7×10⁵dynes/cm², or 2×10⁵ to about 5×10⁵ dynes/cm².

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances. In some embodiments, the polymer comprises 20 wt. % to90 wt. % of the formulation.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer, versus non-polymer). For example in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, incorporation of chain transfer or chaincapping agents and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel that includes a high molecular weight polymer tends tocoagulate or solidify more quickly than a polymeric composition thatincludes a low-molecular weight polymer. Polymeric gel formulations thatinclude high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel that includes low-molecularweight polymers. In various embodiments, the molecular weight of thepolymer can be a wide range of values. The average molecular weight ofthe polymer can be from about 1000 to about 10,000,000; or about 1,000to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 toabout 100,000; or about 20,000 to 50,000 g/mol.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to high viscosity, similar to thatof a paste, depending on the molecular weight and concentration of thepolymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, dripping, injecting,or painting. Different viscosities of the gel will depend on thetechnique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and may have a longerdegradation time). Typically, when the polymers have similar componentsbut different MWs, a gel with a high molecular weight provides astronger matrix and the matrix takes more time to degrade. In contrast,a gel with a low molecular weight degrades more quickly and provides asofter matrix. In various embodiments, the gel has a molecular weight,as shown by the inherent viscosity, from about 0.10 dL/g to about 1.2dL/g or from about 0.10 dL/g to about 0.40 dL/g. Other IV ranges includebut are not limited to about 0.05 to about 0.15 dL/g, about 0.10 toabout 0.20 dL/g, about 0.15 to about 0.25 dL/g, about 0.20 to about 0.30dL/g, about 0.25 to about 0.35 dL/g, about 0.30 to about 0.35 dL/g,about 0.35 to about 0.45 dL/g, about 0.40 to about 0.45 dL/g, about 0.45to about 0.55 dL/g, about 0.50 to about 0.70 dL/g, about 0.60 to about0.80 dL/g, about 0.70 to about 0.90 dL/g, about 0.80 to about 1.00 dL/g,about 0.90 to about 1.10 dL/g, about 1.0 to about 1.2 dL/g, about 1.1 toabout 1.3 dL/g, about 1.2 to about 1.4 dL/g, about 1.3 to about 1.5dL/g, about 1.4 to about 1.6 dL/g, about 1.5 to about 1.7 dL/g, about1.6 to about 1.8 dL/g, about 1.7 to about 1.9 dL/g, and about 1.8 toabout 2.1 dL/g.

In some embodiments, when the polymer materials have differentchemistries (e.g., high MW DLG 5050 and low MW DL), the high MW polymermay degrade faster than the low MW polymer.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, or from about 15 cps to about 75 cps at room temperature. Thegel may optionally have a viscosity enhancing agent such as, forexample, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereof,Carbopol, poly-(hydroxyethylmethacrylate),poly-(methoxyethylmethacrylate), poly(methoxyethoxyethyl-methacrylate),polymethyl-methacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400,PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG3350, PEG 4500, PEG 8000 or combinations thereof.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (e.g.,PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyetherurethane, or a combination thereof.

In some embodiments there is a method for making an implantable drugdepot. The method may comprise combining a biocompatible polymerrecovered according to methods described in this application and atherapeutically effective amount of active pharmaceutical ingredient ora pharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.

In various embodiments, the drug depot comprising the activepharmaceutical ingredient can be made by combining a biocompatiblepolymer and a therapeutically effective amount of active pharmaceuticalingredient or pharmaceutically acceptable salt thereof and forming theimplantable drug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: an active pharmaceuticalingredient and other therapeutic agent(s) and other optional additivessuch as radiographic agent(s), etc. in dissolved or dispersed form. Thisresults in a polymeric matrix region containing these species aftersolvent removal. In other embodiments, a solution containing solventwith dissolved or dispersed therapeutic agent is applied to apre-existing polymeric region, which can be formed using a variety oftechniques including solution processing and thermoplastic processingtechniques, whereupon the therapeutic agent is imbibed into thepolymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: an activepharmaceutical ingredient, optional additional therapeutic agent(s),radiographic agent(s), and so forth. The resulting mixture is thenshaped into an implantable drug depot. The mixing and shaping operationsmay be performed using any of the conventional devices known in the artfor such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, the active pharmaceutical ingredient mayundergo substantial degradation under ordinary thermoplastic processingconditions. Hence, processing is preferably performed under modifiedconditions, which prevent the substantial degradation of the therapeuticagent(s). Although it is understood that some degradation may beunavoidable during thermoplastic processing, degradation is generallylimited to 10% or less. Among the processing conditions that may becontrolled during processing to avoid substantial degradation of thetherapeutic agent(s) are temperature, applied shear rate, applied shearstress, residence time of the mixture containing the therapeutic agent,and the technique by which the polymeric material and the therapeuticagent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the drug depot. Conversely, in anotherembodiment, the biocompatible polymer can be precompounded with thetherapeutic agent under conditions of reduced temperature and mechanicalshear. This precompounded material is then mixed with, for example, aradio-opacifying agent, also under conditions of reduced temperature andmechanical shear, and the resulting mixture is shaped into the drugdepot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear, in various embodiments, thePGLA or PLA can be premixed with the radio-opacifying agent attemperatures of about, for example, 150° C. to 170° C. The therapeuticagent is then combined with the premixed composition and subjected tofurther thermoplastic processing at conditions of temperature andmechanical shear that are substantially lower than is typical for PGLAor PLA compositions. For example, where extruders are used, barreltemperature, volumetric output are typically controlled to limit theshear and therefore to prevent substantial degradation of thetherapeutic agent(s). For instance, the therapeutic agent and premixedcomposition can be mixed/compounded using a twin screw extruder atsubstantially lower temperatures (e.g., 100-105° C.), and usingsubstantially reduced volumetric output (e.g., less than 30% of fullcapacity, which generally corresponds to a volumetric output of lessthan 200 cc/min). It is noted that this processing temperature is wellbelow the melting points of the therapeutic agent because processing ator above these temperatures will result in substantial therapeutic agentdegradation. It is further noted that in certain embodiments, theprocessing temperature will be below the melting point of all bioactivecompounds within the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet) is cooled. Examples of cooling processesinclude air cooling and/or immersion in a cooling bath. In someembodiments, a water bath is used to cool the extruded depot. However,where a water-soluble therapeutic agent such is used, the immersion timeshould be held to a minimum to avoid unnecessary loss of therapeuticagent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired. Insome embodiments, the drug depot has a burst release surface thatreleases about 10%, 15%, 20%, 25%, 30%, 35%, 45%, to about 50% of thedrug over 24 or 48 hours.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, an active pharmaceuticalingredient is used and mixed or sprayed with the PLGA or PEG550 polymer,and the resulting depot may be formed by extrusion and dried.

In some embodiments, the drug depot comprises the at least twobiodegradable polymers recovered and/or purified according to methodsdescribed herein in a wt % of about 99.5%, 99%, 98%, 97%, 96%, 95%, 94%,93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%,79%, 78%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 65%, 60%, 55%, 50%, 45%,35%, 25%, 20%, 15%, 10%, or 5% based on the total weight of the depotand the remainder is active and/or inactive pharmaceutical ingredients.

In some embodiments, the at least two biodegradable polymers recoveredaccording to methods described in this application comprisepoly(lactic-co-glycolide) (PLGA) or poly(orthoester) (POE) or acombination thereof. The poly(lactic-co-glycolide) may comprise amixture of polyglycolide (PGA) and polylactide and in some embodiments,in the mixture, there is more polylactide than polyglycolide. In variousembodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactideand 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, the drug particle size, which may be in powderedform, is from about 5 to 30 micrometers, however, in various embodimentsranges from about 1 micron to 250 microns may be used. In someembodiments, the biodegradable polymer comprises at least 50 wt. %, atleast 60 wt. %, at least 70 wt. %, at least 80 wt. % of the formulation,at least 85 wt. % of the formulation, at least 90 wt. % of theformulation, at least 95 wt. % of the formulation or at least 97 wt. %of the formulation. In various embodiments, the biodegradable polymerparticle size, which may be in powdered form is from about 5 to 30micrometers, however, in various embodiments ranges from about 1 micronto 300 microns may be used. In some embodiments, the at least onebiodegradable polymer and the active pharmaceutical ingredient are theonly components of the pharmaceutical formulation.

In some embodiments, at least 75% of the particles of the drug and thepolymer have a size from about 10 micrometer to about 300 micrometers.In some embodiments, at least 85% of the particles have a size fromabout 10 micrometer to about 300 micrometers. In some embodiments, atleast 95% of the particles have a size from about 10 micrometer to about300 micrometers. In some embodiments, all of the particles have a sizefrom about 10 micrometer to about 300 micrometers.

In some embodiments, at least 75% of the particles of the drug and thepolymer have a size from about 20 micrometer to about 180 micrometers.In some embodiments, at least 85% of the particles have a size fromabout 20 micrometers to about 180 micrometers. In some embodiments, atleast 95% of the particles have a size from about 20 micrometer to about180 micrometers. In some embodiments, all of the particles have a sizefrom about 20 micrometer to about 180 micrometers. In some embodiments,at least 80% of the particles have a size from 5 microns to about 100microns on a volume basis.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. A method for preparing at least two polymershaving a residual monomer content of less than 5%, the method comprisingmixing the at least two polymers in a solvent to form a polymericmixture, the at least two polymers having similar solubilities in thesolvent, the polymeric mixture comprising at least one residual monomerand the polymeric mixture maintained at a pH in the range from 4-6,wherein the at least two polymers comprise a first polymer that ispolylactide (PLA) and a second polymer that is polyglycolide (PGA) andwherein the polymeric mixture contains more PLA than PGA; and adding anantisolvent to the polymeric mixture so as to separate the at least twopolymers from the polymeric mixture, the antisolvent maintained at a pHof about 7, wherein the residual monomer is soluble in the antisolventand the at least two polymers are insoluble in the antisolvent.
 2. Amethod according to claim 1, wherein the first polymer and the secondpolymer of the at least two polymers are added separately to anddissolved in the solvent to form a polymer blend in the mixture.
 3. Amethod according to claim 1, wherein the separation of the at least twopolymers further comprises at least decanting, centrifugation,microfiltration, ultrafiltration, sieving or a combination thereof thepolymeric mixture to obtain the at least two polymers having low monomercontent.
 4. A method according to claim 1, further comprising drying theat least two polymers by evaporation with air or nitrogen orfreeze-drying.
 5. A method according to claim 1, wherein the polymericmixture or the separated at least two polymers comprise at least threepolymers and/or co-polymer blends.
 6. A method according to claim 1,wherein the residual monomer content is from 0.1 to less than 5% w/w orv/v, and the at least two separated polymers have a particle size fromabout 5 micrometers to 500 micrometers.
 7. A method according to claim1, wherein (i) the solvent comprises n-hexane, cyclohexane, heptanes,methylene chloride, ethyl acetate, acetone or combinations thereof; or(ii) the antisolvent comprises water, ethanol, methanol, isopropylalcohol, or mixtures thereof.
 8. A method according to claim 1, whereinthe polylactide content is at least 75% based on the total amount ofpolylactide and polyglycolide.
 9. A method according to claim 1, whereinthe monomer content of the at least two separated polymers is less than0.1% w/w or v/v.
 10. A method according to claim 1, wherein thepolymeric mixture further comprises a dispersant comprising a gas or asurfactant.
 11. A method according to claim 10, wherein the surfactantis an anionic, a cationic, an ampholitic, a non-ionic surfactant or acombination thereof.
 12. A method according to claim 1, furthercomprising recovering the separated at least two polymers and forming adrug depot from the at least two recovered polymers by hot meltextrusion, co-extrusion, multi-layer extrusion, rotational molding,injection molding or casting.
 13. A method for preparing at least twopolymers having a residual monomer content of less than 5%, the methodcomprising adding an antisolvent to a mixture of at least two polymersdissolved in a solvent so as to precipitate the at least two polymersfrom the solvent, each of the at least two polymers having at least oneresidual monomer; wherein the residual monomer is soluble in theantisolvent, and wherein the precipitated polymers have a particle sizefrom about 5 to about 30 micrometers.
 14. A method according to claim13, wherein a first polymer, a second polymer, and a third polymer ofthe at least two polymers are added separately to and dissolved in thesolvent to form a polymer blend in the mixture.
 15. A method forpreparing at least two polymers according to claim 13, wherein the atleast two polymers are removed from the solvent and anti-solvent so asto recover the at least two polymers having low residual monomer contentof less than 0.5% v/v or w/w.
 16. A method for reducing residual monomercontent of at least two polymers in a mixture, the method comprisingadding an anti-solvent to the mixture so as to precipitate the at leasttwo polymers from the mixture, wherein the residual monomer is solublein the antisolvent and the at least two polymers are insoluble in theantisolvent, wherein the at least two polymers are removed from thesolvent and anti-solvent so as to recover the at least two mixedpolymers having low residual monomer content of less than 1% w/w, andwherein the recovered polymers have a particle size from about 5 toabout 30 micrometers.
 17. A method according to claim 6, wherein the atleast two separated polymers have a particle size from about 5micrometers to 30 micrometers.